Chronic ethanol produces many neurological disorders, including memory and cognitive impairments. Alterations in hippocampal synaptic transmission may underlie the effects of ethanol on learning and memory. It has been suggested that the effects of ethanol on CNS function may be mediated by neurosteroids, which are synthesized de novo in brain. Both ethanol and neurosteroids influence excitatory and inhibitorysynaptic transmission by interacting with N-methyl-d-aspartate (NMDA)- and gamma-aminobutyric acid receptors. However, it is not clear how chronic ethanol alters the modulatory effects of neurosteroids on hippocampal synaptic function that is important for memory processing. The proposal will focus on pregnenolone sulfate (PREGS), a potent memory-enhancing neurosteroid, and its interaction with ethanol on NMDA receptor-mediated synaptic transmission and potentiation. The hypothesis being tested is that NMDA receptor-mediated synaptic responses to PREGS are altered by chronic intermittent ethanol (CIE) treatment. Field excitatory post synaptic potentials will be measured from CA1 neurons in hippocampal slices prepared from ethanol-nai've and CIE treated rats. The effect of CIE treatment on PREGSinduced changes in NMDA-receptor mediated synaptic transmission and long-term potentiation will be investigated. Furthermore, the persistence of these alterations will be examined in neuronal slices from rats withdrawn from CIE treatment. Finally, it will be determined whether alterations in kinase activity are involved in the interactions of ethanol and PREGS on long-term potentiation. Collectively, the experiments will advance our understanding of changes in neurosteroid modulation of synaptic function that may be important to the CNS actions of ethanol.